Abstract
A defining feature of the brain is the ability of its synaptic contacts to adapt structurally and functionally in an experience-dependent manner. In the human cortex, however, direct experimental evidence for coordinated structural and functional synaptic adaptation is currently lacking. Here, we probed synaptic plasticity in human cortical slices using the vitamin A derivative all-trans retinoic acid (atRA), a putative treatment for neuropsychiatric disorders such as Alzheimer's disease. Our experiments demonstrated that the excitatory synapses of superficial (layer 2/3) pyramidal neurons underwent coordinated structural and functional changes in the presence of atRA. These synaptic adaptations were accompanied by ultrastructural remodeling of the calcium-storing spine apparatus organelle and required mRNA translation. It was not observed in synaptopodin-deficient mice, which lack spine apparatus organelles. We conclude that atRA is a potent mediator of synaptic plasticity in the adult human cortex.
Highlights
The ability of neurons to express plasticity by responding to specific stimuli with structural and functional changes is critical for physiological brain function (Citri and Malenka, 2008)
We evaluated the role of the actin-modulating protein synaptopodin (Mundel et al, 1997), an essential component of the spine apparatus organelle (Deller et al, 2003), which is a key regulator of synaptic plasticity in the rodent brain (Deller et al, 2003; Segal et al, 2010; Vlachos et al, 2013) and has recently been linked to the cognitive trajectory in human aging (Wingo et al, 2019)
No significant differences in spontaneous excitatory postsynaptic currents (sEPSCs) amplitudes were observed between the two groups (Figure 5A,B). Consistent with these findings, anisomycin blocked the observed atRAmediated increases in dendritic spine head and synaptopodin cluster sizes, whereas the sizes of synaptopodin-positive and synaptopodin-negative spine heads remain significantly different (Figure 5C, D). These results demonstrate that all-trans retinoic acid (atRA)-mediated plasticity requires mRNA translation to trigger coordinated changes in synaptic strength, spine head size, and synaptopodin cluster properties in cortical slices prepared from the adult human brain
Summary
The ability of neurons to express plasticity by responding to specific stimuli with structural and functional changes is critical for physiological brain function (Citri and Malenka, 2008). Direct experimental evidence for coordinated structural and functional synaptic changes in the adult human cortex is lacking (Mansvelder et al, 2019; Verhoog et al, 2016). It remains unclear whether the structural and functional properties of human cortical neurons adapt to those in the rodent brain. All-trans retinoic acid (atRA), which is used clinically in dermatology and oncology (Dobrotkova et al, 2018; Hu et al, 2009), has been studied for its neuroprotective and plasticity-promoting effects in animal models (Chen et al, 2014; Koryakina et al, 2009). Alterations in retinoic acid-mediated synaptic plasticity have been reported in neurons derived from inducible
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